RT Journal Article
SR Electronic
T1 Synergistic effect of curcumin and cisplatin via downregulation of thymidine phosphorylase and ERCC1
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.111.071316
DO 10.1124/mol.111.071316
A1 Yun-Wei Lin
A1 Min-Shao Tsai
A1 Shao-Hsing Weng
A1 Ya-Hsun Kuo
A1 Yu-Fan Chiu
YR 2011
UL http://molpharm.aspetjournals.org/content/early/2011/04/14/mol.111.071316.abstract
AB Curcumin (diferuloylmethane), a phenolic compound obtained from the rhizome of Curcuma longa, is known to have antiproliferative and antitumor properties. Thymidine phosphorylase (TP), an enzyme of the pyrimidine salvage pathway, is considered an attractive therapeutic target and its expression could suppress cancer cell death induced by DNA damage agents. Excision repair cross-complementary 1 (ERCC1) is a protein involved the process of nucleotide excision repair. The ERCC1 gene is expressed at high levels in cancers and has been associated with resistance to platinum-based chemotherapy. In this study, the effects of curcumin on TP and ERCC1 expression induced by cisplatin in non-small cell lung cancer (NSCLC) cell lines was investigated. Exposure of the NSCLC cells to various concentrations of curcumin (5−40 μM) downregulates the mRNA and protein levels of TP and ERCC1 through destabilization of the mRNA and proteins via a mechanism involving inactivation of MKK1/2-ERK1/2. Depletion of endogenous TP or ERCC1 expression by transfection with specific small interfering RNAs significantly decreases cell viability in curcumin-exposed NSCLC cells. Curcumin enhances the sensitivity of cisplatin treatment for NSCLC through inactivation of ERK1/2 and by decreasing the TP and ERCC1 protein levels. Enhancement of ERK1/2 signaling by constitutively active MKK1/2 (MKK1/2-CA) causes an increase in TP and ERCC1 protein levels and promotes cell viability after cotreatment with curcumin and cisplatin. Enhancement of the cytotoxicity to cisplatin by administration of curcumin is mediated by downregulation of the expression levels of TP and ERCC1 and by inactivation of ERK1/2.